Male infertility

Abhishek Yadav
Introduction
• Approximately 15% of couples are unable to conceive after one year of
unprotected intercourse. 1 in 6 as childless

• A male factor is solely responsible in about 20% of infertile couples and

contributory in another 30-40%

• Azoospermia- complete absence of sperm from the ejaculate

• Incidence- about 1% of all men and approximately 15% of infertile men

Azoospermia
Pre-testicular
Testicular
Post-testicular

Other Classification:-
Obstructive azoospermia
Nonobstructive azoospermia (NOA)
40% will have obstructive azoospermia

60% cases Non-obstructive azoospermia

Non-obstructive azoospermia is more common type

Obstructive azoospermia Causes:

• Congenital bilateral absence of the vas deferens

• Obstruction of ejaculatory and epididymal ducts

• Atresia of the seminal vesicles

• Various infections of the genitourinary tract resulting in obstruction

• Pelvic and inguinal procedures leading to a complete blockage such as a

bilateral vasectomy
Obstructive azoospermia

• Spermatogenesis is often normal

• Surgical correction of the blockage

• Most cases also need other assisted reproductive techniques

Nonobstructive azoospermia

• More common type

• Exact pathology often idiopathic

• Severe defects in spermatogenesis, which are frequently due to primary

testicular failure or dysfunction

• Dysfunction of the pituitary or hypothalamus.

Etiologies

Etiologies fall into three general categories:

• Pretesticular

• Testicular

• Post-testicular
• Pretesticular :- endocrine abnormalities that adversely affect spermatogenesis

• Testicular- intrinsic disorders of spermatogenesis inside the testes

• Post-testicular- obstruction of the ductal system

Pretesticular Causes

Congenital or acquired

Kallmann syndrome: Defects seen at the level of the hypothalamus

• Failure of GnRH hormone secretion (hypogonadotropic hypogonadism)

• Occurs due to failure in the migration of GnRH releasing neurons to the

olfactory lobe (decreased sense of smell)

• Hyperprolactinemia: Hyperprolactinemia is the excessive production of prolactin
hormone.
• Hyperprolactinemia results in sexual dysfunction due to inhibition of secretion of
GnRH from the hypothalamus, which leads to impaired fertility.
• In these patients, there is decreased spermatogenesis due to testicular abnormalities
on both sides
 Non-obstructive azoospermia (NOA) causes and
reproductive hormone profiles
Testicular

• Klinefelter Syndrome: It is characterized by a tall eunuchoid phenotype, decreased

facial and pubertal hair, decreased penis size, hard testicles, decreased cognitive

abilities, and decreased testosterone levels.

• These patients have azoospermia

• During testicular sperm extraction, spermatozoa are seen in almost 69% of men
Abnormal spermatogenesis

1. Point mutation in single gene: eg cystic fibrosis

2. Azoospermic factor (AZF): microdeletion

AZF region sub divide into

AZF a: germ cell aplasia/ sertoli cell only histology

AZF b : maturation arrest at primary spermatocyte stage

AZF c : ass.with hypospermatogenesis

 Post-testicular Causes of Azoospermia

• Congenital bilateral absence of the vas deferens (CBAVD): Its incidence is 1% amongst

infertile men. It mainly occurs due to mutations in the cystic fibrosis transmembrane

regulator gene (CFTR)

• Vasal obstruction: Incidences of unintended vasal obstruction are usually seen after

corrective surgeries for inguinal canal hernias. The testicular size remains normal on

examination, but the epididymis feels firm

Post-testicular Causes of Azoospermia cont..

• Obstruction of epididymis: Obstruction of the epididymis is present in Young

syndrome, which is a triad of chronic sinusitis, bronchiectasis, and obstructive

azoospermia.

• Obstruction of the ejaculatory ducts: Obstruction of the ejaculatory ducts of

unilateral or bilateral
Evaluation of Patient

•History

• TICS:

• T stands for toxins.

• I for infectious/inflammatory disease.

• C for childhood history

• S for sexual history

Toxins
• Endocrine Modulators -Medications may affect the ratio of estrogen to androgen through a variety of
mechanisms
• molecular similarity to estrogen

• increased estrogen synthesis

• increased aromatase activity

• dissociation of steroids from sex hormone-binding globulin (SHBG)

• decreased testosterone synthesis

• competitive and noncompetitive binding to steroid receptors

• decreased synthesis of adrenal steroids

• induction of hyperprolactinemia
Medications

• Antiandrogens -Bicalutamide, flutamide, and nilutamide

• Antihypertensive -Spironolactone

• Protease inhibitors- Indinavir

• Nucleoside reverse transcriptase inhibitors –stavudine

• Corticosteroids, especially in adolescence

• Exogenous estrogen
Recreational drugs

• Cannabis -decreases plasma testosterone in a dose-dependent and duration dependent manner

• Heavy chronic alcohol intake -increase aromatization of testosterone to estradiol

• Cigarette smoking

• worsens bulk seminal parameters.

• Increased seminal oxidative stress parameters

• abnormal ratio of protamines 1 and 2 ,with evidence of atypical protamine 2 expression

Antihypertensives

• Can cause erectile dysfunction

• Calcium channel blockers

• inhibits expression of mannose-ligand binding receptors

• preventing sperm from attaching to the zona pellucida

• ACE inhibitors appear to improve sperm motility through a presumptive

effect on seminal plasma kinins
• 2.5 mg of lisinopril daily increased sperm count, motility, and morphology
Antipsychotics
• Most common mechanism of action for antipsychotic drugs is antagonism of dopamine

• Causes loss of libido

• Elevation of prolactin levels, most acute for risperidone and to a lesser extent olanzapine

• Selective serotonin reuptake inhibitors (SSRIs)

• anorgasmia

• delayed or absent ejaculation

Antibiotics

• Tetracycline binds mature sperm

• direct toxicity on sperm function oxidative stress mechanism

• In animals that high doses of nitrofurantoin reduced epididymal sperm

density and sperm motility

 Cytotoxic Chemotherapeutics
• Suppress briskly proliferating population of cells.
• Spermatogenic suppressive effects-dose and time dependent
• Higher doses and longer durations of therapies results in permanently impaired fertility
• Alkylating agents such as the nitrogen mustard cyclophosphamide
• Doxorubicin, vincristine, and prednisone,
• Cisplatin, etoposide, and bleomycin
• Sperm DNA damage can be detected at least up to 2 years after chemotherapy
• Cryopreservation of sperm before treatment with cytotoxic chemotherapeutic agents
• Bacille Calmette-Guérin into the bladder for superficial transitional cell carcinoma resulted in a
significant decrease in sperm concentration and motility
 Thermal Toxicity

• Scrotal temperature -2° C to 4° C below core body temperature

• Clothing, physical activity, and body posture such as whether the legs are crossed or not

in a sitting position all change scrotal temperature

• occupational exposure

• Laptop computers radiate heat, and researchers have studied the effects of these devices

on scrotal temperature
 Radiation

• Ionizing radiation- germ cell loss and Leydig cell dysfunction

• chances of having future offspring were lessened by radiation doses to the testes of

7.5 Gy and above

• If the radiation field is proximal to the testis and the dose is sufficient, sperm production

may be diminished even if the testis is shielded

 I: infection and inflammation
• Infections of the testis, epididymis, prostate, and urethra may lead to male infertility through
anatomic and functional means
• Common organisms affecting the prostate include Escherichia coli, Pseudomonas aeruginosa, and
Klebsiella, Proteus, and Enterococcus species
• Typical epididymal organisms include Neisseria gonorrhoeae, Chlamydia trachomatis and
E. coli
• Infections of the testis may include the mumps, Coxsackievirus B, N. gonorrhoeae, C.
trachomatis, E. coli, P. aeruginosa, and Klebsiella, Staphylococcus, and Streptococcus species
• Mumps orchitis

• Bilateral disease 36% result in Testicular atrophy

• Infertility occurs in 13%

• Mycobacterium tuberculosis may affect any reproductive organ and cause scarring of
the vas deferens and epididymis
• *vasal calcification: TB,syphilis, gonorrhoea,schistosomiasis,chronic UTI. DM.
Childhood diseases

Hydroceles and hernias repaired during childhood

• Low but discrete incidence of complications causing vasal obstruction

• Rate of testis atrophy after pediatric inguinal hernia was 0.3%

• Testis Torsion

• Half of men will develop adverse spermatogenic effects

• 36% to 39% of men will have sperm concentrations below 20 million/mL

• 11% of men will develop antisperm antibodies

 Cryptorchidism
• Dysfunction of the seminiferous epithelium

• Leydig cell steroidogenesis

• Ultrastructural defects

• Widely recognized that surgical correction of undescended testes after puberty -minimal effect on
bulk semen analysis parameters .
• Age before puberty at which orchidopexy results in optimal effect in reproductive potential has not
been definitively established.

• Prudent to recommend orchidopexy before 10 years of age from a reproductive perspective

 Male Reproductive Physical Examination
• Most effectively performed with the patient standing

• low examining table or chair, as some men will develop syncope during palpation of the
scrotum
• Examining the Scrotum

• Visual observation

• One or both sides may be hypoplastic

• substantially larger than the other, suggesting a reactive hydrocele or tumor.

• varicocele
Male Reproductive Physical Examination cont..

Epididymis is typically difficult to appreciate

• if it is easily palpated, it is likely engorged, suggests obstruction

Testis size
• well established to correlate with sperm production

• assessed by calipers often referred to Seager orchidometer

• long axis of the testis is gently grasped between the jaws of the calipers,

• measurement of 4.6 cm or less is associated with spermatogenic impairment

• Compare the examiner’s palpation findings with a string of ellipsoids of increasing size

with marked volumes

• A volume of 20 mL or less is considered low

• Directly measured by ultrasonography of the scrotum

 Examining the Spermatic Cord

• Palpation whether the vas deferens is palpable, and whether a varicocele is present.

• Firm cordlike structure /compressibility of the vessels

• Absence of the vas can be a difficult physical sign to identify

• Meacham’ maxim -vas disappears from the examiner’s fingers three times, the clinician
confident that the vas is absent. (Randall Meacham)
Examining the Spermatic Cord cont..

Unilateral absence of the vas deferens

• complete lack of wolffian ductal development on that side, including renal
agenesis (79%)
• If both vasa are absent, high likelihood of a cystic fibrosis gene mutation

Renal agenesis in 11% of men with congenital bilateral absence of the vas deferens.

Best modality to diagnose absence of vas deferens: clinical examination

 Varicocele

Varicocele is the most commonly encountered nonductal surgically addressable pathologic

entity

• Grade I-not palpable or visible,can only be detected by radiographic evaluation such as

Doppler ultrasound

• Grade II-palpable but not visible

• Grade III-visible by the examining physician through the rugae of the scrotum

Incidence of varicocele in infertile males to be between one-third and one-half

• PENIS: abnormalities include phimosis, meatal displacement in hypospadias or

epispadias, and significant penile curvature

• Semen must be deposited proximal to the cervical os for optimal chance of

reproduction

• DRE: seminal vesicles cannot typically be palpated; if palpable, engorgement and

possible ejaculatory ductal obstruction

• Midline cysts such as müllerian duct cysts,can obstruct the ejaculatory ducts
 Endocrine evaluation
• Minimal evaluation includes the assessment of serum FSH and testosterone levels, which
reflect germ cell epithelium and Leydig cell status respectively
• Spermatogenesis is highly dependent on intratesticular testosterone synthesis

• Either 280 ng/dL or 300 ng/dL as a threshold for adequate androgenization in a man.

• In the healthy man,

• 30% to 44% of circulating testosterone is bound to SHBG

• 54% to 68% is loosely bound to albumin

• 0.5% to 3.0% is unbound

• Bioavailable testosterone demonstrates a marked circadian rhythm in young, healthy men,

• peak in the early morning and trough in the late afternoon

• SHBG is altered in a variety of medical conditions.

• Practical method of determining bioavailable testosterone is to calculate it from total

testosterone, SHBG, and albumin
• SHBG displays an opposing circadian rhythm in men of all ages, with a peak in the late
afternoon and a trough in the early morning
Sertoli cell products inhibin B and activin
• regulate pituitary follicle-stimulating hormone (FSH)

• respectively inhibiting and stimulating its release

• With depopulation of Sertoli cells

• inhibin levels decrease and FSH consequently increases

• measuring inhibin B directly is a more accurate assessment of spermatogenic function

• 96% of men with obstructive azoospermia had FSH assay values of 7.6 IU/L or less and
testis long axis greater than 4.6 cm

Ratio of total testosterone to estradiol below 10 : 1 is suggested to indicate reproductive

dysfunction
Semen analysis

Minimum of two analyses separated by 2 to 3 weeks for assessment

Historically, men were instructed to wait 2 to 5 days after an ejaculation to submit a

sample for semen analysis

More recent studies suggest that a single day of abstinence is optimal for assessing

bulk seminal parameters

 Semen volume
• Most frequently used threshold value for volume is 1.0 mL to initiate evaluation for seminal
hypovolemia.
• Aspermia, dry ejaculate, and anejaculation refer to the condition in which no fluid is discharged from
the urethra during male orgasm.
• If aspermia or seminal hypovolemia is observed, a postejaculatory urinalysis is performed to identify
retrograde ejaculation.
• Transrectal ultrasonography (TRUS) is conducted to evaluate whether ejaculatory ductal
obstruction may be present .
• Seminal hypervolemia with an ejaculate volume exceeding 5 mL
Normospermia Normal semen volume
Aspermia No semen volume
Hypospermia Semen volume < 1.5 ml
Hyperspermia Semen volume > 5.0 ml
Azoospermia No spermatozoa in semen
Oligospermia Sperm concentration <15 M/ml
Polyzoospermia High sperm concentration, >200M/ml
Asthenozoospermia <40% motile or < 32% Progressive motile
Hematospermia blood cell present in semen
Necrozoospermia “dead” sperm
OAT Oligo-astheno-teratozoospermia
 Secondary Semen Assays

Assay for antisperm antibodies :

Conditions associated with antisperm antibody formation include vasectomy, testis

trauma, orchitis cryptorchidism, testis cancer, and varicocele

Two direct assays are available:

• 1.the mixed antiglobulin reaction (MAR) test.

• 2.the immunobead assay

 Pyospermia Assays:

• The Papanicolaou stain may be used to differentiate leukocytes from immature

germ cells based on nuclear morphology .

• The current consensus threshold for leukocytes according to the WHO laboratory

manual is 1 million/mL
•Tertiary and Investigational Sperm Assays

• Sperm DNA Integrity Assays :

•Sperm DNA is six times more compact than in somatic cells.

• Fragmentation or disturbances in DNA arrangement lead to aberrations in sperm function,

fertilization, implantation, and pregnancy

 TUNEL Assay
The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL).

• Detect sperm head DNA fragmentation .

• Ratio of TUNEL-positive sperm to all sperm and expressed as a percentage.

• Comet Assay: Like the TUNEL assay, the comet assay, also referred to as the single-cell gel

electrophoresis assay.

Denatured Sperm DNA Assays:

• Assay for sperm head DNA structure is the Sperm Chromatin Structure Assay (SCSA)
 Sperm Ultrastructural Assessment

• Sperm motility is dependent on the ultrastructural arrangement of microtubules in the tail

with a peripheral array of nine pairs and a central two microtubules connected by dynein arms.

• This “9 + 2” architecture is shared with cilia, and genetic disorders affecting it can manifest

as respiratory pathology associated with male reproductive dysfunction, referred to as the

immotile cilia syndrome, primary ciliary dyskinesia (PCD), or Kartagener syndrome.

• Sperm Fluorescence in situ Hybridization : employs fluorescent-labeled primers

that bind specifically to each chromosome in the sperm, allowing measurement of

sperm aneuploidies that are of major clinical importance

• KARTAGENER SYNDROME: chronic sinusitis and bronchiectasis,situs

inversus, and infertility

Genomic Assessment

Karyotype:

American Urological Association Best Practice Statement on the Optimal Evaluation of the

Infertile Male recommends that

• Genetic testing including karyotype be performed in all males with azoospermia

caused by spermatogenic dysfunction

• Those with severe oligospermia defined as less than 5 million sperm/ml

Y Chromosome Microdeletion Testing
• Region in the long arm of the Y chromosome- critical to the formation of sperm i.e
AZF (azoospermia factor)
• Microdeletions of AZFc appear to be associated with spermatogenic impairment but
not failure
• AZFa and AZFb microdeletions cause significant pathology of the testis resulting in
diminishing low likelihood of sperm retrieval
• Genetic screening of the CFTR in men with CBAVD and their partners identifies the
presence of severe mutations such as ΔF508 that may result in clinically overt cystic
fibrosis in offspring
 Imaging in the evaluation of male infertility

• TRUS:

• Employs the 5- to 7-MHz probe .

• Diagnosis of ejaculatory ductal obstruction

• Azoospermia in conjunction with low seminal volume is encountered

• TRUS imaging evidence of ejaculatory duct obstruction includes

• Anteroposterior seminal vesicle diameter of greater than 1.5 cm with or without a midline
prostatic cyst
• ED diameter > 2.3mm
• MRI with an endorectal coil can be used to evaluate anatomic features consistent
with ejaculatory ductal obstruction
• Abdominal imaging in the evaluation of the infertile male is primarily used to study
whether renal sequelae of congenital vasal maldevelopment is present
• Cranial MRI allows assessment of whether hyperprolactinemia is associated with
an anatomic pituitary lesion (distinguish between microadenomas and
macroadenomas)
 Testicular biopsy

•Diagnostic:

• Azoospermia with suspected obstruction as the cause

• Normal testicular size and consistency

• Normal serum FSH levels

• Suspected testicular failure (occasionally)

• Small-volume testes, High serum FSH level.

• not indicated in the initial diagnostic evaluation of the infertile man

Specimens should be placed in a fixative solution such as Bouin’s, Zenker’s or

glutaraldehyde

Formalin should not be used as it may disrupt the tissue architecture

The most common complication of testis biopsy is hematoma.

Hematomas can be large and may require drainage

The most serious complication associated with testis biopsy is inadvertent biopsy of the

epididymis.
Germ cells are lacking entirely
and only Sertoli cells are visible in
the germinal epithelium. Sertoli
cell–only syndrome/Germinal
aplasia

Visualization of a mature sperm

head is typically sufficient to
confirm completion of the stages
of spermatogenesis
•Vasography

• Gold Standard Test for assessing the patency of vas

• Provides anatomic details of the

• Vas deferens

• Seminal vesicles

• Ejaculatory ducts

• Determination of the site of obstruction in the azoospermic patient

• Ideally performed at the time of anticipated reconstruction

INDICATIONS:(Absolute)

1. Azoospermia, plus

2. Complete spermatogenesis with many mature spermatids on testis biopsy, plus

• At least one palpable vas

Scenarios :

1. Absence of sperm in vasal fluid indicates obstruction on the testicular side of the
vasotomy site, most likely an epididymal obstruction

2. Copious vasal fluid containing many sperm indicates vasal or ejaculatory duct
obstruction.

3. Copious thick, white fluid without sperm in a dilated vas indicates secondary
epididymal obstruction
Retrograde Ejaculation

• Bladder neck must first close while temporal neural sequencing first causes closure
of the external sphincter to create a high pressure compartment that is emptied with its
subsequent opening.
• Primary treatment modalities include retrieval of retrograde ejaculated sperm and
increasing resistance at the bladder neck with sympathomimetic agents.
• Sympathomimetic agents such as synephrine, pseudoephedrine, ephedrine, or
phenylpropanolamine
 ANEJACULATION

• Due to lack of seminal emission and projectile ejaculation.

• Due to neurologic and include retroperitoneal lymph node dissection, pelvic surgery,

multiple sclerosis, transverse myelitis, congenital neural tube defects, diabetes

mellitus, and spinal cord injury .

• Electroejaculation, may result in sufficient sperm for IUI or IVF .

 Spinal cord injuries at a level of T6 or above, stimulation may cause autonomic

dysreflexia, an uninhibited sympathetic reflex accompanied by headache,

diaphoresis, hypertension, bradycardia, and diaphoresis, which may be life

threatening.

 Treatment with nifedipine and during the procedure with monitoring of cardiac

activity and blood pressure

TURED : In Ejaculatory duct obstruction
Surgical techniques in sperm retrieval
EPIDYDIMAL SPERM RETRIEVAL
 Varicocelectomy
 Varicocelectomy is by far the most commonly performed operation for the treatment
of male infertility
 Varicocele is found in approximately 15% of the general population
 35% of men with primary infertility and in 75% to 81% of men with secondary
infertility
 Variococelectomy can also improve Leydig cell function resulting in increased
testosterone levels
 Hydrocele formation is the most common complication due to lymphatic obstruction
 Procedures in Artificial reproductive techniques
Intra Uterine Insemination (IUI): Involves injecting processed sperm using a small

catheter through the cervix into the uterine cavity

In Vitro Fertilization (IVF): sperm and ovum are mixed outside the body and transfer

into the uterus after fertilization.

Intracytoplasmic Sperm Injection ( ICSI)

Sperm preparation Methods:

• Simple washing

• Swim-up technique

• Density gradient
• Motile sperm organelle morphology examination (MSOME) :is a nondestructive

method of assessing sperm nuclear morphology, and a sperm chosen by this

method of high magnification visual inspection could be subsequently used in

IVF techniques
Thank You!